1. Field of Invention
The present invention relates to the biological prosthetic materials including heart valves, vessels, pericardium, dura mater, skin, amniotic membrane, umbilical cord, muscle tendons, ligaments, fascias and gut of mammalian origin used as a whole or in a part as grafts for various organs and tissues. This invention is particularly suitable for replacement or repair of heart valves, blood vessel, pericardial tissues and other body membranes.
2. Description of the Prior Art
Bodily tissue replacement surgery has been established over the past 30 years, particularly in the area of valve and organ replacement. The field has been shared between biological and mechanical replacement in the repair of tissues and organs. In the area of biological replacement of heart valves, glutaraldehyde treated porcine heart valves, have been used as an improvement over mechanical valves. Carpentier A et at., J Torah Cardiovasc Surg 58:467-82, (1969). Dystrophic calcification is chief cause of failure of bioprosthetic heart valves derived from glutaraldehyde-treated porcine aortic valves, Schoen F J et al. Human Pathol; 16:549-59(1985). Schoen F J et at. Cardiovasc Clin; 18:289-17 (1988). Ibrahim M et al. J Thorac Cardiovasc Surg; 108:221-30(1994).
Calcific deposits in either porcine valves or bovine pericardial valves are evident in residual connective cells of bioprosthetic tissue within 48 hours of subcutaneous implantation. Initial nucleation sites are located in cell membranes, cell nuclei, and intracellular organelles, such as mitochondria. Cell-associated deposits of calcium increase in size and number over time after implantation. These deposits obliterate cells, dissect among collagen bundles, and ultimately form gross nodules similar to those associated with clinical failures. Direct collagen involvement subsequently occurs. Schoen F J et al. In: Bodnar E, ed. Surgery for heart valve disease: The proceedings of the 1989 symposium. 679-85 (1990). The components of a valve can be divided into two parts with respect to their degree of antigenicity: (1) cells, water soluble proteins, mucopolysaccharides, and structural glycoproteins which had a high degree of antigenicity and. (2) collagen and elastin which appear to be less antigenic. In some instances, collagen can induce an immunological response. Carpentier A et al. J Thorac Cardiovasc Surg, 58:467-82(1969).
Concerning the prevention of calcification, various chemical techniques have been used but the results are inconclusive. Inhibition of mineralization of bioprosthetic valves implanted subcutaneously in small size animals has been achieved through pretreatment with various chemical components Carpentier A et al., Circulation; 70 (suppl 1): 165-8(1984). Lentz D J et al., Trans Am Soc Artif Intern Organs, 28:494-8 (1982) and with systemic or local controlled release of diphosphonate, Webb C L et al., Ann Thorac Surg, 46:309-16(1988). Levy R J et al., Circulation 71:349-56(1985). T6 (sodium dodecyl sulfate) processing inhibits the onset of intrinsic mineralization in glutaraldehyde-fixed xenograft tissue, Lentz D J et al. Cohn L W, Galluci V, eds. Cardiac biotissue grafts. Proceedings of the Second International Symposium. New York: Yorke Medical Books., 306-19(1982). T6 treatment did not significantly affect the onset and degree of bioprosthetic calcification, Thurbrikar M J et al., Trans Am Soc Artif Intern Organs, 29:245-9 (1983). Toluidine blue is the calcium retarding agent employed in the Medtronic-Intact porcine valve. Although the biochemical mechanism by which the toluidine blue process modifies the calcification is unknown. It is presumed that toluidine blue treatment inhibits or retards calcification of collagen, while the calcification of cellular components remains unaffected Valence M et al., Bodnar E, ed., Surgery for heart valve disease: The proceedings of the 1989 symposium, 668-76(1990). Preincubation in aluminum chloride (AICl.sub.3) significantly inhibits calcification of bovine pericardium in 60 days after being subcutaneously implanted in rats. Iron also inhibits calcification of bioprosthetic tissue Schoen F J et at., Bodnar E, ed. Surgery for heart valve disease: The proceedings of the 1989 symposium. London: ICR Publishers, 679-85(1990). Other methods to reduce calcification of biotissue grafts, such as acyl-azide treatment, Petite H et at., J Biomed Mater Res., 24:179-87(1990) and dye mediated photo oxidization, Moore M A et al., J Biomed Mater Res, 28:611-8(1994) have been reported. It also has been reported that L-Glutamic acid posttreatment significantly reduces the calcification of glutaraldehyde treated bioprosthetic material subcutaneously implanted in rats Grabenvorger M et al. J Biomed Mater Res, 26:1231-40(1992). According to unpublished work by the inventors, it is not apparent that temperature has a positive effect on calcium mitigation of biotissue grafts, however it has been reported that pretreatment of porcine aortic valve in glutaraldehyde at high temperature (50.degree. C.) alone mitigates calcification in both subcutaneous and circulatory models Carpentier S M et at., Ann Thorac Surg, 69:S332-8(1995). It has been reported that .alpha.-amino oleic acid (AOA) posttreatment prevents calcification of glutaraldehyde treated bioprosthetic heart valves, Girardot M N et al., Trans Soc Biomater., 14:114(1991). In all valves implanted in mitral position in young sheep for 5 months, AOA-treated valves had morphologic features suggesting generalized tissue degradation, including structural loosening, surface roughening, and deep cuspal collections of erythrocytes, Gott J P et al., Ann Thorac Surg, 53:207-16(1992). Moreover, the treatment with .alpha.-amino oleic acid did not prevent the calcification of aortic wall in sheep study Chen W et al., Circulation 90:323-9(1994). Researchers have found that the tissue extraction process significantly reduces the propensity of xenograft calcification in vivo, Vesely I. et al., Ann Thorac Surg, 60:S359-64(1995). The extent of glutaraldehyde cross-linking is clearly important, although the specific mechanisms by which glutaraldehyde fixation facilitates mineralization are not understood Webb C L et at., Ann Thorac Surg ;46:309-16(1988). The slow release of residual (unbound) glutaraldehyde from the prosthesis over a period of time after implantation reinforces the host plasma calcium-acid bound complex. This acid-plasma calcium complex promotes further mineralization when glutaraldehyde plays no more role as the primary factor for nucleation of calcification. Chanda J., Ann Thorac Surg, 60:S339-42(1995)
In cells modified by aldehyde cross-linking or mechanical injury, cell membranes are disrupted (leading to increased permeability), and mechanisms for calcium extrusion are no longer fully functional. Moreover, high energy phosphates (particularly ATP) required to fuel these mechanisms are unavailable. Thus, calcium accumulation occurs unimpeded with a dramatic increase in intracellular calcium Schoen F J et al., Cardiovasc Clin,; 18/2:28917(1988); Webb C L, et al., Ann Thorac Surg, 46:309-16(1988). When glutaraldehyde treatment is used alone, elimination of highly antigenic substances such as cellular elements and water soluble proteins, does not prevent the calcification of glutaraldehyde-treated biotissue grafts implanted in adult rats. Moreover, further treatment with glutarahyde does not prevent calcification. Chanda J., Ann Thorac Surg, 60:S339-42(1995). Inactivation of residual glutaraldehyde and unbound aldehyde moieties on the surface of the tissue gratis, either with amino compound like chitosan (a biopolymer) or glycine+gentamicin completely prevents the calcification of glutaraldehyde-treated biotissue grafts implanted subdermally in adult rats (120-150 g), Chanda J., Ann Thorac Surg 60:S339-42; Chanda J., Artif Organs, 18:408-10(1994). However inactivation of free impaired aldehydes either with chitosan, or glycine+gentamicin, or chitosan in combination with glycine and gentamicin does not prevent the calcification of glutaraldehydetreated biotissue grafts when implanted subdermally in weanling (3-week-old, 30-50 g) rats.
Heparin has potent anti-growth effect in smooth muscle cells Hoover R L et al., Circ Res, 47:578-83(1980). It also has been shown that heparin binds to the surface of cells Hiebert L M et at., Thromb Res, 8:195-04(1976) Different reactions used to break down heparin are known Shively J et al., Biochemistry, 15:3932-42. (1976). Method for covalent binding of heparin to artificial surfaces has been developed, Larm O et at., Biomat Med Dev Art Org, 11:161-73(1983) At present heparin coated tube is widely used as cardiopulmonary bypass circuit in open heart surgery. Heparin as one of various forms of glycosaminoglycan may be used in preparation of artificial skin substitute (wound dressing) U.S. Pat. No. 5,489,304 to Orgill et al. issued Feb. 6, 1996.